Glucocorticoid-induced osteoporosis is a major clinical problem for which no therapy is currently available. This is in part due to a lack of knowledge about the direct actions of glucocorticoids in bone. It appears that in vivo one of the major effects of glucocorticoids is the inhibition of bone formation, and in vitro studies have shown that glucocorticoids inhibit bone collagen synthesis. Studies from our laboratory have indicated that insulin-like growth factor (IGF) I and II are among the most prevalent growth factors secreted by bone cells and are potent stimulators of bone collagen synthesis. Recently, we found that cortisol decreases IGF I synthesis and IGF II concentrations in cultures of 21 day fetal rat calvariae and of osteoblast-enriched (Ob) cells from 22 day fetal rat parietal bone. Cortisol also inhibited IGF II binding to Ob cells. In contrast, parathyroid hormone (PTH) and cAMP inducers stimulated skeletal IGF I synthesis. It is our hypothesis that glucocorticoids act by decreasing the synthesis and binding of IGF's in bone cells, and these actions are reversible. Over the course of the next five years we propose to (1) define the exact effects of cortisol on bone formation using histomorphometric analysis, study its mechanisms of action on the inhibition of type 1 bone collagen synthesis at the transcriptional level and define its effects on bone collagen degradation; (2) study the mechanism of action of cortisol in bone and examine the precise level of action on IGF I and II synthesis, and on IGF receptor expression in Ob cells; and (3) determine if PTH and other agents known to stimulate skeletal IGF I synthesis reverse the inhibitory actions of cortisol on IGF I synthesis, and define hormones that reverse the cortisol-induced decrease in skeletal IGF II concentrations and binding to Ob cells. The agents found to modify the inhibitory actions of cortisol on IGF synthesis and binding will be tested to determine if they reverse the inhibitory actions of cortisol on parameters of bone formation in vitro. These studies will provide valuable information on the mechanism of action of cortisol in bone and possibly will form the foundation for logical therapeutic alternatives in glucocorticoid-induced osteopenia.